Explainer: multiple sclerosis

Author

Disclosure statement

Tobias David Merson receives funding from the National Health and Medical Research Council (NHMRC), Stem Cells Australia, an Australian Research Council (ARC) special initiative in stem cells, Multiple Sclerosis Research Australia (MSRA) and the CASS Foundation.

Multiple sclerosis is a neurological disease affecting almost 25,000 Australians and more than 2.4 million people worldwide. It’s one of the leading causes of disability in young adults.

Typically, the illness is first experienced as an episode of blurred vision, numbness or tingling in the arms or legs. These symptoms usually subside for a time, only to recur or present in other forms such as pain, paralysis, fatigue, slowed thinking or memory problems.

The most common form of multiple sclerosis occurs as cyclical episodes of relapse and remission, but the disease can also manifest in an unrelenting progressive form with increasing severity of symptoms.

The causes of multiple sclerosis

Although the cause of multiple sclerosis remains unknown, we do know about a number of factors that increase risk. Gender, for instance, has a large effect: the incidence in females is three times higher than in males.

Genes play a role too, but there doesn’t appear to be one that’s entirely responsible for the illness. Rather, many different genes appear to contribute a small risk.

Surprisingly, geography also plays a major role in multiple sclerosis incidence. The further you live from the equator, the higher your risk of developing multiple sclerosis.

In Australia, the effect of latitude is remarkable: Tasmanians are seven times more likely to develop the disease than people living in far north Queensland. The amount of sun exposure and associated vitamin D production is believed to underlie this geographical gradient.

Causes of symptoms and treatment

Multiple sclerosis symptoms are caused by a failure of nerve cells in the brain and spinal cord to transmit signals normally.

Several processes contribute to this abnormal signal transmission, but a key trigger is the loss of a fatty substance that normally wraps around and insulates nerve fibres, known as myelin. When the amount of myelin around a nerve fibre diminishes, the speed and efficiency of signalling is drastically reduced.

Preventing the loss of myelin or promoting its regeneration could preserve the function of nerve cells and stop them from becoming irreversibly damaged. But the trigger for the onset of myelin loss is poorly understood as most people start to have symptoms a long time after this starts.

Once myelin loss is established, the immune system mistakenly responds to the substance as foreign, destroying it as if it were an invading pathogen.

One theory is that a viral infection alters the immune system, triggering it to identify myelin as foreign. White blood cells then enter neural tissue through the bloodstream and mount an attack on myelin, marking it for destruction. Scavenger cells called macrophages follow, recognise these “eat me” signals and internalise and digest the myelin coating.

For the last 40 years, the main drugs for treating multiple sclerosis have reduced the immune response with the aim of preventing myelin loss. Although these therapies cannot cure the disease, they are effective in reducing the severity and frequency of symptoms of relapsing-remitting multiple sclerosis.

Despite their benefits, current drugs don’t entirely prevent myelin loss, especially as the disease progresses. So a new approach gaining traction is developing new classes of drugs to promote the body’s natural regenerative ability to produce new myelin.

A new discovery

To understand how to produce new myelin requires a brief primer on what myelin actually is (this gets a little complex but bear with me).

Myelin is an integral part of a specialised cell type called an oligodendrocyte. When the immune system destroys myelin, this also leads to the death of the oligodendrocyte.

Fortunately, this degenerative process signals for new myelin to be produced by sending chemical signals to immature progenitor cells to mature into new oligodendrocytes. In other words, immature oligodendrocytes present in the adult brain can divide and mature into new ones on demand.

New research from my laboratory deepens our understanding of the types of progenitor cells that can make oligodendrocytes after myelin is lost. In our recently published study, we showed brain stem cells that normally mature primarily into nerve cells can change their “career path” to produce large numbers of oligodendrocytes instead. In some areas of the brain, these brain stem cells actually play a much greater role in regenerating myelin than do immature oligodendrocytes.

We also found that brain stem cells produce thicker myelin that restores nerves to a youthful appearance, as if the damage had never been inflicted. Although immature oligodendrocytes make new myelin, it’s much thinner than the healthy myelin observed in the undamaged nervous system.

Now we want to understand how and why the response of immature oligodendrocytes and brain stem cells to myelin loss differs.

Generating drugs that can coax immature oligodendrocytes to respond more like brain stem cells could help them regenerate myelin more efficiently. This could go a long way to helping restore nerve function when myelin loss escapes our best attempts at prevention.